Osteoblastic differentiation and P-glycoprotein multidrug resistance in a murine osteosarcoma model

A recent study of multidrug resistance (MDR) 1 gene transfected osteosarcom a cells found a cause-effect relationship between increased expression of P -glycoprotein (P-gp) and a low aggressive phenotype, However, several exper imental and clinical studies have observed contradictory findings in that P -gp expression has been associated with tumour progression. In the present study, we characterized P-gp-positive and P-gp-negative single-cell clones of a murine osteosarcoma, to further investigate the relationship between P -gp expression and changes in cell phenotype, Although these clones were al l selected by doxorubicin (DOX) exposure, they were heterogeneous with resp ect to MDR1 gene expression. The P-gp-positive clones revealed MDR phenotyp e, whereas the P-gp-negative clones showed no resistance to drugs. Morpholo gical and functional analysis showed that both the P-gp-positive and P-gp-n egative clones were more differentiated than the parent cells in terms of e nhanced activity of cellular alkaline phosphatase, an increase in well-orga nized actin stress fibres and enhanced osteogenic activity. Moreover, these subclones all displayed a decrease in malignant potential such as oncogeni c activity, tumour growth rate and metastatic ability, regardless of their P-gp status. These results indicate that the observed osteoblastic differen tiation and less aggressive phenotype in DOX-selected osteosarcoma cells ma y not only be explained by the direct effect of P-gp, and accordingly, cons ideration of the effect of DOX, as well as P-gp, appears to be important. ( C) 2000 Cancer Research Campaign.